Despite an increased understanding of the molecular pathogenesis of cancer, the treatment of squamous cell cancer of the oral cavity (OSCC) remains a formidable problem. Advanced stage disease is often met with recurrence, metastasis and death despite multi-modality treatment, including chemotherapy. In patients with OSCC, profound immunosupression of immune functions occur, in addition to resistance of tumors to immune effector cells. The mechanisms responsible are unknown, but it is likely that chemotherapeutic drugs modify expression of Fas and/or other apoptotic molecules on tumor cells as well as natural killer (NK), T and dendritic (DC) cells. Since p53 is also involved in apoptosis of oral cancer cells, it is important to elucidate the role of p53 expression in influencing the survival of death of these cells after chemotherapy. To address these issues, we propose three Specific Aims: Aim 1. To define the ability of anti-proliferative drugs to modify immunologically and apoptotically important molecules in oral cancer and identify the factors important in oral cancer survival. Aim 2. To identify the effects of these agents on T-cells, NK cells, and DC's apoptosis. Aim 3. To evaluate the mechanism by which adenoviral p53 gene transfer modifies sensitivity to apoptotic signaling pathways. It is the central thesis of this proposal that events within the tumor microenvironment are critically important to the success of anti-proliferative or immunotherapies and that focusing on precise apoptotic mechanisms involved in cellular death at the tumor site will lead to modified and improved strategies in the treatment of patients with oral cancer.